Three Salk discoveries land on 2013 "best of the year" lists

As 2013 came to a close, three Salk Institute discoveries won national recognition by being named to prestigious
scientific "best of the year" lists. Science magazine lauded the groundbreaking work manipulating stem cells in
Juan Carlos Izpisua Belmonte's lab, naming it a runner-up for 2013 Breakthrough of the Year. And team findings
on the complexity of the human brain, research led by Fred "Rusty" Gage and Joe Ecker, earned the number four
spot on a year-end list compiled by Tom Insel, director of the National Institute of Mental Health.

On a "ten best" list that included gene-editing, brain-imaging and sleep
studies, the editors of Science praised researchers' success in getting
pluripotent stem cells to grow into tiny "organoids" in the lab. "It's still
a challenge to coax stem cells to grow into specific tissues, let alone
into organized structures," the magazine's editors wrote. "This year,
researchers did just that, in spectacular style, growing a variety of
'organoids' in the lab: liver buds, mini-kidneys, and, most remarkably,
rudimentary human brains."

At the Salk Institute, Izpisua Belmonte and his team were able to grow
the "mini-kidneys," an accomplishment reported earlier in Nature Cell
Biology. Building on research that had indicated stem cells could be used
to create precursors of kidney cells, the Salk team became the first to coax
human stem cells into forming actual three-dimensional cellular structures
similar to those found in human kidneys.

"Attempts to differentiate human stem cells into renal cells have
had limited success," said Izpisua Belmonte, a professor in Salk's Gene
Expression Laboratory and holder of the Roger Guillemin Chair. "We have
developed a simple and efficient method that allows for the differentiation
of human stem cells into well-organized 3D structures of the ureteric bud,
which later develops into the collecting duct system."

In an initial testing of their protocol, Izpisua Belmonte' s team used
induced pluripotent stem cells (iPSCs) collected from a patient with a
genetic disorder known as polycystic kidney disease (PKD) and found
that they were able to produce kidney structures from the patient-derived
iPSCs. The team's accomplishment holds great promise for treating kidney
disease, since these organs rarely recover function once they are damaged.
For the year-end list compiled by NIH's Tom Insel, Salk scientists Fred
Gage and Joe Ecker were lauded for their work revealing new complexities
in the human brain in two separate papers published in Science.

"2013 will be the year when we begin to realize how much the brain
differs from other organs," Insel wrote. "We already knew that cells in the
brain express (translate into protein) more of the genome and use more
energy than any other organ. But two discoveries this year really made the
case for the human brain as not only the most mysterious but the most
exceptional of organs."

One discovery came from the lab of Fred Gage, professor in the Laboratory
of Genetics and holder of the Vi and John Adler Chair for Research on
Age-Related Neurodegenerative Disease. Using single-cell sequencing,
Gage and his colleagues showed that the genomic structures of individual
neurons differ from each other even more than expected. The scientists
took a high-level view of the entire genome, looking for large deletions
and duplications of DNA called copy number variations (CNVs). What
they discovered was that as many as 41 percent of the cells in the frontal
cortex have at least one mutation, with a million DNA bases either
duplicated or deleted.

"These are mutations not seen in blood cells (which are the basis for
all psychiatric genetic studies)," Insel wrote, "or in neurons elsewhere in
the brain."

A discovery by Joe Ecker, professor and director of Salk's Genomic
Analysis Laboratory and holder of the Salk International Council Chair in
Genetics, added to the unfolding appreciation of the brain's complexity.
When the discovery was first published, NIH director Francis Collins
described it as revealing "an entirely new perspective on a fundamental
issue in biology or medicine."

Working with Salk professor Terry Sejnowski, holder of Salk's Francis
Crick Chair, Ecker and his team showed that the landscape of DNA
methylation, a particular type of epigenomic modification, is highly
dynamic in brain cells during the transition from birth to adulthood,
helping to understand how information in the genomes of cells in the brain
is controlled from fetal development to adulthood.

"The entire DNA strand consists of only four bases: cytosine, guanine,
adenine and thymine," Insel wrote in his year-end roundup. "Whereas in
most cells in the body silencing occurs where cytosine and guanine are
adjacent, brain cells follow a different set of rules with all the base pairs
involved. This means that the mechanisms by which experience influence
biology are completely different in brain cells compared to blood cells or
liver cells."

Underscoring the value of the research performed by the two Salk
teams, Insel concluded, "The lesson is that we cannot use peripheral cells
to know what is happening in the brain."